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J. Biol. Chem., Vol. 281, Issue 19, 13309-13316, May 12, 2006

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Perturbation of rRNA Synthesis in the bap28 Mutation Leads to Apoptosis Mediated by p53 in the Zebrafish Central Nervous System^*

From the Laboratory of Molecular Genetics, NICHD, National Institutes of Health, Bethesda, Maryland 20892

Zebrafish is a powerful vertebrate model system for using forward genetics to elucidate mechanisms of early development. We have used chemical mutagenesis to screen for mutants that show defects in the CNS. Here we describe the isolation of the bap28 mutation that leads to abnormalities in the brain starting at midsomitogenesis stages. Mutant embryos display excess apoptosis primarily in the central nervous system (CNS) and die by days 6-7 after fertilization. The mutation was positionally cloned and shown to affect a gene that encodes a large protein with high similarity to the uncharacterized human protein BAP28 and lower similarity to yeast Utp10. Utp10 is a component of a nucleolar U3 small nucleolar RNA-containing RNP complex that is required for transcription of ribosomal DNA and for processing of 18 S rRNA. We show that zebrafish Bap28 likewise is required for rRNA transcription and processing, with a major effect on 18 S rRNA maturation. We suggest that bap28 is required for cell survival in the CNS through its role in rRNA synthesis and processing. Inhibition of p53 protein expression in bap28 mutants led to embryos with morphologically normal appearance, suggesting that p53 is involved in triggering apoptosis in the bap28 mutant CNS. The bap28 mutation provides a genetic approach to study the role of ribosome biogenesis in the development of a vertebrate embryo.

Received for publication, February 27, 2006

^* This research was supported in part by the Intramural Research Program of the NICHD, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Supported in part by the Japan Society for the Promotion of Science.

² To whom correspondence should be addressed: Laboratory of Molecular Genetics, NICHD/National Institutes of Health 9000 Rockville Pike Bldg., 6B Rm. 413, Bethesda, MD 20892. Tel.: 301-496-4448; Fax: 301-496-0243; E-mail: idawid{at}nih.gov.

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